Epithelial ovarian cancer, which accounts for ˜90% of all ovarian cancer, is the most common cause of death from gynecologic malignancies and originates from the single layer of epithelial cells on the surface of the ovary (Holschneider et al., Semin. Surg. Oncol. 19:3-10, 2000; Orsulic et al., Cancer Cell 1:53-62, 2002). It has been proposed that repeated stimulation of these ovarian surface epithelial (OSE) cells in response to injury caused by ovulation may play an etiologic role in the development of epithelial ovarian cancer (reviewed in Auersperg et al., Semin. Oncol. 25:281-304, 1998).
Injury repair responses are controlled by a variety of growth factors, including the insulin-like growth factors (IGFs). The IGF system is a complex network of IGF peptides (IGF-I and IGF-II), transmembrane receptors that mediate the biological responses to IGFs, and high affinity binding proteins that modulate IGF actions. IGF binding protein (IGFBP) functions are multifaceted, and include limiting the bioavailability of IGFs, targeting IGFs to distinct tissues, local regulation of IGF action at the cellular level, and newly recognized IGF-independent effects. This regulatory system is further controlled by the activation of proteases specific for individual IGFBPs. For example, the IGF-sequestering and, therefore, inhibitory function of IGFBP-4 is abrogated by enzymatic cleavage in the central portion of the IGFBP-4 molecule, resulting in the release of IGF-I. An IGF-dependent IGFBP-4 protease produced by a variety of cell types, including human fibroblasts and ovarian granulose cells was recently identified as pregnancy-associated plasma protein-A (PAPP-A) (Lawrence et al., Proc. Natl. Acad. Sci. USA 96:3149-3153, 1999). This protein had no previously identified function, but is elevated in serum during pregnancy due to increased placental expression. It is now recognized that PAPP-A functions outside of pregnancy as well. Although its exact physiological role is unknown, PAPP-A appears to be involved in repair responses in the vasculature and the reproductive ovary.